Prostaglandins (PGs) are a series of physiologically active substances having the prostanoic acid skeleton. Being a member of this class, prostaglandin E2 (PGE2) is generated from arachidonic acid by a four-stage synthesis reaction called the arachidonic acid cascade and is known to have a variety of actions including a pain triggering action, inflammatory response, a cell protecting action, uterine contraction, peristaltic promotion of the digestive canal, antihypnotic action, a gastric acid secretion suppressing action, a hypotensive action, an angiogenic action, a diuretic action, etc. Conventionally, as therapeutics for diseases associated with such PGs, non-steroidal anti-inflammatory drugs (NSAIDs) are extensively used that suppress prostaglandin production by means of inhibiting cyclooxygenase (COX) which is one of the synthases participating in the arachidonic acid cascade; NSAIDs, however, present the problem that on account of their inhibiting the upstream stage of the arachidonic acid cascade, various side-effects including gastrointestinal disorders occur as complications. In view of such side-effects, drugs are desired that inhibit the binding of PGE2 to PGE2 receptors.
The PGE2 receptors exist in four subtypes, EP1, EP2, EP3 and EP4, which are distributed widely among a variety of tissues.
The actions of PGE2 as mediated by the EP4 receptor are involved in inflammatory responses (including immune inflammatory response), relaxation of smooth muscle, pain triggering, differentiation of lymphocytes, enlargement or proliferation of mesangial cells, secretion of gastrointestinal mucus, for example. Hence, EP4 receptor antagonistic drugs are considered to be promising as anti-inflammatory and/or analgesic drugs for diseases associated with the receptor EP4-mediated PGE2 actions (such as, for example, inflammatory diseases and diseases that involve various kinds of pain). Further, it has recently been reported that the action of PGE2 mediated by the receptor EP4 on the surfaces of dendritic cells or T cells causes activation of Th1 cells or Th17 cells; the activated Th1 or Th17 cells cause tissue destruction and evoke inflammation, eventually triggering multiple sclerosis and various other immune diseases; hence, the EP4 receptor antagonistic drugs are also attracting researchers' attention as therapeutics for such immune diseases (Non-Patent Documents 1 and 2). In this regard, it has been verified that a plurality of EP4 receptor antagonists having different skeletons are actually effective in EAE (experimental autoimmune encephalomyelitis) models which are animal models for immune diseases typified by multiple sclerosis (Non-Patent Documents 2 and 3).
Thus, compounds that are antagonistic against the EP4 receptor-mediated actions of PGE2 hold promise as drugs for the treatment of diseases involving various inflammations including acute and/chronic as well as immune inflammations, and various studies have heretofore been conducted on EP4 receptor antagonistic drugs.
EP4 receptor antagonistic drugs so far known include, for example, compounds represented by the following formula (Patent Documents 1, 2 and 3):
(wherein ring A represents phenyl or pyridyl; for details, see the documents cited above).
As EP4 receptor antagonists, compounds represented by the following formula are also known (Patent Document 4):
(for the symbols in the formula, see the document cited above).
As EP4 receptor antagonists, compounds represented by the following formula are also known (Patent Document 5):
(for the symbols in the formula, see the document cited above).
As EP4 receptor antagonists, compounds represented by the following formula are also known (Patent Document 6):
(for the symbols in the formula, see the document cited above).
As EP4 receptor antagonists, compounds represented by the following formula are also known (Patent Document 7):
(for the symbols in the formulae, see the document cited above).
As EP4 receptor antagonists, compounds represented by the following formula are also known (Patent Document 8):
(for the symbols in the formula, see the document cited above).
As EP4 receptor antagonists, compounds represented by the following formula are also known (Patent Document 9):
(wherein ring D is a group represented by:
for details see the document cited above).
As EP4 receptor antagonists, compounds represented by the following formula are also known (Patent Document 10):
(for the symbols in the formula, see the document cited above).
As EP4 receptor antagonists, compounds represented by the following formula are also known (Patent Document 11):
(for the symbols in the formula, see the document cited above).
Neither of these prior art documents disclose or suggest 4-alkynylimidazole derivatives.